Stamler et al. U.S. Pat. No. 6,057,367 is directed to treating mammals for infections or for conditions associated with pathologically proliferating mammalian cell growth (for example, certain cancers, restenosis, benign prostatic hypertrophy) by administration of a manipulator of nitrosative stress (an impetus for NO or NO2 group attachment to proteins, nucleic acids or other biological molecules) to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells.
Stamler et al. U.S. application Ser. No. 09/695,934 discloses use of NO donors to prevent the occurrence of restenosis following angioplasty, to inhibit platelets to prevent coagulation and thrombus formation, to treat angina in patients at risk for coagulation and thrombus formation, to inhibit microbes, to treat impotence, asthma, cystic fibrosis, hypoxia and ischemic disorders, heart failure, stroke, arthritis, ARDS, hypertension, neurodegeneration, painful crisis of sickle cell disease, cancer and any pathological proliferation of cells and any NMDA related injury. The invention is directed to C-nitroso compounds and use thereof as NO donors.
Gaston, Stamler and Griffith U.S. application Ser. No. 08/403,775 is directed to use of inhibitors of S-nitrosothiol breakdown to treat asthma.
Numerous enzymes have been shown to break down S-nitrosothiols in vitro. These include (a) thioredoxin system, (b) glutathione peroxidase, (c) gamma glutamyl transpeptidase, (d) xanthinei oxidase, (e) alcohol dehydrogenase Class III, and (f) other classes of alcohol dehydrogenase.
In respect to alcohol dehydrogenases including alcohol dehydrogenase Class III (also known as glutathione-dependent formaldehyde dehydrogenase), see the following publications which present in vitro data: Kuwada, M., et al. J. Biochem. 88, 859–869 (1980); Jensen, D. E., et al., Biochemical Pharmacology 53, 1297–1306 (1997); Jensen, D. E., et al., Biochem. J. 331, 659–668 (1998).
Despite the in vitro results referred to above, the current perspective is that thiols, ascorbate and copper ions break down S-nitrosothiols in vivo. However, there has been no work heretofore demonstrating how S-nitrosothiols are broken down in vivo.
It has not heretofore been known that inhibition of glutathione-dependent formaldehyde dehydrogenase mediates NO donor therapy, nitrosative stress and NO bioactivity in vivo.